Kappa selective opioid receptor antagonist

Abstract

A selective kappa opioid receptor antagonist, (S)-3-Fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide or a pharmaceutically acceptable salt thereof, useful for treating ethanol use disorder withdrawal, and anxiety and/or depression, or schizophrenia as independent comorbid conditions.

1. 3-Fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
       2. (S)-3-Fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof. 
     
     
       3. A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
       4. A pharmaceutical composition comprising a compound of  claim 2 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
       5. A method of selectively antagonizing kappa opioid receptors in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       6. A method of treating ethanol use disorder in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       7. A method of treating an anxiety disorder selected from panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder, specific phobia, and posttraumatic stress disorder in a patient in need thereof which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       8. A method of treating an anxiety disorder selected from panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder, specific phobia, and posttraumatic stress disorder; and ethanol use disorder in a patient in need thereof which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       9. A method of treating a depressive illness selected from major depression, dysthymia and bipolar disorder, in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       10. A method of treating a depressive illness selected from major depression, dysthymia and bipolar disorder, and ethanol use disorder in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       11. A method of treating an anxiety disorder selected from panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder, specific phobia, and posttraumatic stress disorder, and a depressive illness selected from major depression, dysthymia and bipolar disorder in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       12. A method of treating an anxiety disorder selected from panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder, specific phobia, and posttraumatic stress disorder; and a depressive illness selected from major depression, dysthymia and bipolar disorder; and ethanol use disorder in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       13. A method of treating schizophrenia in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       14. A method of treating schizophrenia and ethanol use disorder in a patient in need thereof, which comprises administering a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, to said patient. 
     
     
       15. A pharmaceutical composition comprising a therapeutically effective amount of (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a tertiary amine tricyclic norepinephrine reuptake inhibitor selected from amitriptyline, clomipramine, doxepin, imipramine and (+)-trimipramine, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
       16. A method of treating ethanol use disorder and a depressive illness selected from major depression, dysthymia and bipolar disorder, in a patient in need thereof which comprises administering (S)-3-fluoro-4-[4-[2-(3,5-dimethylphenyl)pyrrolidin-1-yl-methyl]phenoxy]benzamide, or a pharmaceutically acceptable salt thereof, and a tertiary amine tricyclic norepinephrine reuptake inhibitor selected from amitriptyline, clomipramine, doxepin, imipramine and (+)-trimipramine, or a pharmaceutically acceptable salt thereof, to said patient.